Scholarly article on topic 'The LIBERTY Study: Design of a prospective, observational, multi-center trial to evaluate the acute and long-term clinical and economic outcomes of real-world endovascular device interventions in treating peripheral artery disease'

The LIBERTY Study: Design of a prospective, observational, multi-center trial to evaluate the acute and long-term clinical and economic outcomes of real-world endovascular device interventions in treating peripheral artery disease Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — George L. Adams, Jihad Mustapha, William Gray, Nick J. Hargus, Brad J. Martinsen, et al.

Background Most peripheral artery disease (PAD) clinical device trials are supported by commercial manufacturers and designed for regulatory device approval, with extensive inclusion/exclusion criteria to support homogeneous patient populations. High-risk patients with advanced disease, including critical limb ischemia (CLI), are often excluded leading to difficulty in translating trial results into real-world clinical practice. As a result, physicians have no direct guidance regarding the use of endovascular devices. There is a need for objectively assessed studies to evaluate clinical, functional, and economic outcomes in PAD patient populations. Study Design LIBERTY is a prospective, observational, multicenter study sponsored by Cardiovascular Systems Inc (St Paul, MN) to evaluate procedural and long-term clinical and economic outcomes of endovascular device interventions in patients with symptomatic lower extremity PAD. Approximately 1,200 patients will be enrolled and followed up to 5 years: 500 patients in the “Claudicant Rutherford 2-3” arm, 600 in the “CLI Rutherford 4-5” arm, and 100 in the “CLI Rutherford 6” arm. The study will use 4 core laboratories for independent analysis and will evaluate the following: procedural and lesion success, rates of major adverse events, duplex ultrasound interpretations, wound status, quality of life, 6-minute walk test, and economic analysis. The LIBERTY Patient Risk Score(s) will be developed as a clinical predictor of outcomes to provide guidance for interventions in this patient population. Conclusion LIBERTY will investigate real-world PAD patients treated with endovascular revascularization with rigorous study guidelines and independent oversight of outcomes. This study will provide observational, all-comer patient clinical data to guide future endovascular therapy.

Academic research paper on topic "The LIBERTY Study: Design of a prospective, observational, multi-center trial to evaluate the acute and long-term clinical and economic outcomes of real-world endovascular device interventions in treating peripheral artery disease"

Accepted Manuscript

The LIBERTY Study: Design of a prospective, observational, multi-center trial to evaluate the acute and long-term clinical and economic outcomes of real-world endovascular device interventions in treating peripheral artery disease

George L. Adams MD, MHS, Jihad Mustapha MD, William Gray MD, Nick J. Hargus PhD, Brad J. Martinsen PhD, Gary Ansel MD, Michael R. Jaff DO

PII: S0002-8703(15)00705-X

DOI: doi: 10.1016/j.ahj.2015.12.013

Reference: YMHJ 5084

To appear in:

American Heart Journal

Received date: Accepted date:

10 April 2015 22 December 2015

Please cite this article as: Adams George L., Mustapha Jihad, Gray William, Hargus Nick J., Martinsen Brad J., Ansel Gary, Jaff Michael R., The LIBERTY Study: Design of a prospective, observational, multi-center trial to evaluate the acute and long-term clinical and economic outcomes of real-world endovascular device interventions in treating peripheral artery disease, American Heart Journal (2015), doi: 10.1016/j.ahj.2015.12.013

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The LIBERTY Study: Design of a prospective, observational, multi-center trial to evaluate the acute and long-term clinical and economic outcomes of real-world endovascular device interventions in treating peripheral artery disease

George L. Adams, MD, MHS *, Rex Healthcare, Raleigh, NC (George.Adams@rexhealth.com)

Jihad Mustapha, MD, Metro Health Hospital, Wyoming, MI (jihad.mustapha@metrogr.org)

William Gray, MD, Columbia University Medical Center, NY, NY (wg2131@mail.cumc.columbia.edu)

Nick J. Hargus, PhD, Cardiovascular Systems Inc., St. Paul, MN (nhargus@csi360.com) Brad J. Martinsen, PhD, Cardiovascular Systems Inc., St. Paul, MN (bmartinsen@csi360.com) Gary Ansel, MD, Riverside Methodist Hospital, Columbus, OH (garyansel@aol.com) Michael R. Jaff, DO, Massachusetts General Hospital, Boston, MA (mjaff@partners.org)

Abbreviated title: LIBERTY peripheral artery disease trial

*Address for correspondence: George Adams, MD., M.H.S Rex Healthcare

4414 Lake Boone Trail, Suite 402 Raleigh, NC 27607

Abstract

Background: The majority of peripheral artery disease (PAD) clinical device trials are supported by commercial manufacturers and designed for regulatory device approval, with extensive inclusion/exclusion criteria to support homogeneous patient populations. High-risk patients with advanced disease, including critical limb ischemia (CLI), are often excluded leading to difficulty in translating trial results into real-world clinical practice. As a result, physicians have no direct guidance regarding the use of endovascular devices. There is a need for objectively assessed studies to evaluate clinical, functional and economic outcomes in PAD patient populations.

Study Design: LIBERTY is a prospective, observational, multi-center study sponsored by Cardiovascular Systems, Inc. (St. Paul, MN) to evaluate procedural and long-term clinical and economic outcomes of endovascular device interventions in patients with symptomatic lower extremity PAD. Approximately 1,200 patients will be enrolled and followed up to 5 years: 500 patients in the "Claudicant Rutherford 2-3" Arm; 600 in the "CLI Rutherford 4-5" Arm; and 100 in the "CLI Rutherford 6" Arm. The study will utilize 4 core laboratories for independent analysis and will evaluate the following: procedural and lesion success, rates of major adverse events, duplex ultrasound interpretations, wound status, quality of life, six-minute walk test, and economic analysis. The LIBERTY Patient Risk Score(s) will be developed as a clinical predictor of outcomes to provide guidance for interventions in this patient population.

Conclusion: LIBERTY will investigate real-world PAD patients treated with endovascular revascularization with rigorous study guidelines and independent oversight of outcomes. This study will provide observational, all-comer patient clinical data to guide future endovascular therapy.

TRIAL REGISTRATION NUMBER: NCT01855412

Keywords: atherectomy, balloon angioplasty, stenting, PAD, peripheral arterial disease, critical limb ischemia

BACKGROUND

The prevalence and economic impact of peripheral artery disease (PAD), a widespread public health concern, continues to rise in part due to an increasing elderly population and the

pandemic of diabetes mellitus. In 2001, in the United States (U.S.) alone, PAD affected 8-12

i . • • 2 million patients , while in 2010 this number was almost 18 million .

The most common symptom of PAD is intermittent claudication (IC), Rutherford categories

1-33. IC is pain caused by inadequate arterial circulation during activity, resulting in a marked deterioration in quality of life (QoL)4. Current medical treatment guidelines recommend supervised exercise and medical therapy in patients with IC. It has been shown that supervised exercise therapy improves walking ability in PAD patients with IC4,5 and has an effect on improving QOL6,7. However, supervised exercise therapy for PAD is currently not reimbursed by third party payers and studies have shown that patients find it difficult to follow an independent exercise regimen . The TransAtlantic Inter-Society Consensus (TASC) II and the American College of Cardiology/American Heart Association guidelines for the management of patients with PAD recommend both exercise therapy and endovascular revascularization as treatment options for IC9. The CLEVER trial demonstrated that supervised exercise and iliac stenting improved walking performance and QoL more than medical therapy alone at 6 months and 18 months10,11. However at 18 months the improvement in peak walking time was similar in the supervised exercise and iliac stenting groups11. Other recent studies found no significant difference between the effectiveness of supervised exercise therapy and endovascular

revascularization after 12 months or 7 years . Based on these findings, most clinicians recommend that patients benefit from the combination of these two treatments.

Critical limb ischemia (CLI), Rutherford stages 4-6, the most severe, limb threatening, and mortal form of PAD, currently affects 2.8-3.5 million people . It has been shown that in CLI patients that do not undergo surgical or endovascular intervention, the patient survival and limb salvage rates are 46% and 54% after 1 year, respectively14. The number of amputations performed annually in the U.S. is estimated at 160,000 to 180,00015. In 2008, 5,790 lower extremity amputations were performed per 100,000 PAD patients in the U.S.16 Between 2000 and 2010, 31.6% of Medicare beneficiaries undergoing lower extremity amputation did not undergo arterial testing in the 12 months preceding amputation . Another study found similar

low utilization with only 27% of Medicare CLI patients undergoing an angiogram prior to

amputation . This is of particular interest since minimally invasive endovascular therapies for PAD such as percutaneous transluminal angioplasty, stents (both bare and drug-eluting), and atherectomy, are available for clinical use. Though historically less durable, these minimally invasive therapies offer inherent advantages over traditional surgical revascularization, such as lower morbidity/mortality, shorter hospital length of stay and considerably less patient discomfort. As the field of endovascular therapy continues to expand, the need for traditional surgical therapies as a primary revascularization strategy appears to be considerably reduced19.

Over the past decade there has been an exponential rise in lower extremity percutaneous

arterial revascularizations with a concomitant reduction in the number of surgical

interventions . From 1998 through 2007, the volume of endovascular lower extremity revascularization (LER) doubled, while the volume of open LER decreased by 67%. Analysis of the Nationwide Inpatient Sample from 1996-2005 revealed population-based rates of acute admissions for PAD decreased by 4.3% per year, open procedures by 6.6% per year, and major

amputations by 6.4% per year, whereas endovascular procedure rates increased by 4.8% per

year . Nationally, endovascular LER interventions quadrupled (8% to 32%) for CLI patients and doubled (26% to 61%) for patients with IC22.

Endovascular treatment options for PAD continue to expand and the choice of revascularization must be considered in the context of the patient's clinical presentation, specific anatomic and lesion characteristics and the optimal device features to ensure success. Currently, the clinical data on the choice of specific treatment methods is sparse and there is no defined standard of care, leaving the choice up to the physician's discretion. Trial designs traditionally focus on regulatory requirements rather than relevant clinical outcomes. Well-designed and executed prospective investigations that track clinically relevant outcomes, including the cost of the endovascular treatments and long term outcomes are required to determine the optimal therapies for patients with PAD, ultimately advancing both treatments and outcomes for PAD patients.

Study Purpose

The purpose of this study is to evaluate acute and long-term clinical, functional and economic outcomes of current endovascular procedures to treat PAD. The LIBERTY study will

include all FDA-approved technologies to treat claudication and CLI. The study objectives are: 1) Evaluate procedural and long-term clinical and economic outcomes for subjects undergoing peripheral endovascular device intervention used to treat lower extremity PAD that includes a target lesion in a native vessel located within or extending into the target area (10 cm above the medial epicondyle to the digital arteries), and 2) Develop LIBERTY Patient Risk Score(s) to predict clinical outcomes and provide additional guidance for interventions in this patient population.

METHODS

Study design summary

LIBERTY is a prospective, observational, multi-center, clinical study examining predictors of clinical outcomes for patients undergoing endovascular treatment of lesions within or extending into the target area (10 cm above the medial epicondyle to the digital arteries). This includes disease in a vessel located within or extending into the distal superficial femoral artery (SFA), popliteal (POP), tibial peroneal trunk (TPT), anterior tibial (AT), posterior tibial (PT), and peroneal tibial (PR) arteries. Twelve hundred patients will be enrolled and divided into 3 study arms based on presenting Rutherford classification. The results will evaluate acute outcomes and all patients will be followed for up to 5 years (see Figure 1).

Study management

Cardiovascular Systems, Inc. (St. Paul, MN, USA) is the sponsor of LIBERTY, which has been registered (NCT01855412; http://www.clinicaltrials.gov). No extramural funding was used to support this work. The authors are solely responsible for drafting and editing of this paper.

Figure 1: LIBERTY Study Design

Site selection

The study will be conducted at up to 100 U.S. sites and site selection will not be randomized. Sites are required to comply with the principles of Good Clinical Practices (GCP) and meet the World Medical Association Declaration of Helsinki requirements. The study will be performed in accordance with FDA requirements set forth in 21 Code of Federal Regulations (CFR) Parts 50 and 56. Sites will be expected to demonstrate the following criteria: 1) Experience in and use of multiple endovascular technologies to treat lower extremity PAD; 2) Research team with adequate, qualified personnel; 3) Adequate patient population; and, 4) Familiarity and accessibility to electronic data capture (EDC). There will be no limitation on physician subspecialty—cardiologists, radiologists, and vascular surgeons may participate in the trial.

Each site will be limited to enrollment of a maximum of 15% of the total study population (or 180 subjects) unless written permission to increase this limit is obtained from the Sponsor and the Institutional Review Board (IRB), if applicable.

Study population

LIBERTY is intended to be an observational study and is not designed to test any specific hypothesis; thus, no power calculations were performed to determine sample size.

Approximately 1,200 patients will be enrolled in this study. The subject will be considered enrolled in the study after the following criteria have been met: 1) Signed written informed consent form (ICF); 2) all of the inclusion and none of the exclusion criteria are met; and, 3) at least one lesion in the target area is treated with an endovascular device. At least one target lesion must be crossed and treated for the subject to be considered enrolled in the study. If during the index procedure, endovascular treatment of the target lesion is converted to surgical therapy, the subject is not considered enrolled in the study, and therefore no study follow-up will be required.

The study cohort will be divided into three study arms according to the most severe clinical syndrome present at the time of study enrollment with the assigned cohort sizes identified: 1) "Claudicant Rutherford 2-3" Arm - 500 subjects; 2) "CLI Rutherford 4-5" Arm -600 subjects; or, 3) "CLI Rutherford 6" Arm - 100 subjects. All efforts will be made to ensure that consecutive patients will be enrolled in the study regardless of the type of endovascular treatment that they may receive.

Eligibility criteria

Subjects must meet all of the inclusion criteria and none of the exclusion criteria listed in Table 1 to be eligible to participate in the study.

Table 1: Eligibility Criteria for LIBERTY Study

Inclusion criteria

1. Subject's age > 18 years.

2. Subject presents with a Rutherford classification of 2 to 6.

3. Subject presents with clinical evidence of PAD requiring endovascular intervention on one or both limbs that includes a target lesion in a native vessel located within or extending into 10 cm above the medial epicondyle to the digital arteries. • If subject presents with bilateral disease, the first limb treated will be considered the target limb. • For subjects with one or more wounds on the target limb, the target lesion(s) should be considered the lesion(s) in the vessel(s) that provide(s) blood flow to the wound(s).

4. Subject has at least one lesion in a native vessel located within or extending into the target area that is crossed and treated with an endovascular device. Note: the Investigator can make an additional attempt to treat a lesion in the target area at a later time point if the initial attempt to treat was unsuccessful. If successful on reintervention, the subject can be enrolled.

Exclusion criteria

1. Subject is unwilling or unable to sign the IRB-approved informed consent form (ICF).

2. Subject is unable to understand or comply with the study protocol requirements.

3. Subject is currently participating in an investigational drug or other device study.

4. Subject requires a conversion from endovascular intervention to a surgical bypass graft for any lesion(s) in the target area, as determined by the Investigator.

5. Subject has an in-stent restenosis in the target area, and this lesion is the only one requiring treatment.

6. Subject is pregnant or planning to become pregnant within the study period.

7. Subject has an anticipated life span of less than one (1) year.

Study endpoints

Since this is an observational study there is not a single primary study endpoint. Instead, six different endpoint measures will be collected and assessed at various time points to gather relevant information about the treatment of PAD. Data will be adjudicated by the angiographic, duplex ultrasound, 6 Minute Walk Test and health economics core laboratories (listed below).

Endpoint 1. Procedural Success and Lesion Success

Procedural success is defined as a final post-procedural result of < 50% residual stenosis for all treated lesions during index procedure without significant angiographic complications (i.e., flow-limiting dissection, perforation, slow/no re-flow, distal embolization, acute vessel closure) as determined by the angiographic core laboratory (SynvaCor/Prairie Educational and Research Cooperative (PERC), Springfield, IL).

Lesion success is defined as a final post-procedural result of < 50% residual stenosis for a given lesion treated during index procedure and without significant angiographic complications as determined by the angiographic core laboratory.

The rates of procedural success and of lesion success will be estimated in the context of logistic regression analysis, and will attempt to quantify the relationship between covariates or sub-group effects and success rates.

Endpoint 2. Rate of Major Adverse Events (MAEs)

The rate of the following MAEs as reported by the investigators will be assessed during the subject's participation in the study: 1) Death within 30 days of index procedure; 2)

Unplanned major (above the ankle) amputation of the target limb; and, 3) Clinically driven target lesion revascularization (TLR) and/or target vessel revascularization (TVR) of the target limb. The angiographic core lab will assess TLR/TVR events.

Correlations between MAEs and each of the following outcomes will be explored: 1) Analysis sub-populations; 2) Number of outflow vessels treated; and, 3) Plaque morphology. The rates of the MAEs will be estimated in the context of logistic regression, and will attempt to quantify the relationship between covariates or sub-group effects and MAE rates. Additionally, time-to-MAE will be compared between treatments within study arms using a Cox proportional-hazards model.

Endpoint 3. Patency Duplex Ultrasonography (DUS)

DUS will be performed at subject follow-up visits and analyzed by the DUS Core Laboratory (VasCore, Massachusetts General Hospital, Boston, MA). This data will be collected for subjects enrolled in the "Rutherford classification 2-3 Arm" to assess arterial patency in treated segments. The rates of the categorical outcomes of the DUS assessments will be estimated in the context of logistic regression, and will attempt to quantify the relationship between covariates or sub-group effects and outcome rates. The correlations between the quantitative outcomes of the DUS assessments and other endpoints, such as the six-minute walk test and Quality of Life (QoL) will be examined in the context of a general linear model.

Endpoint 4. Change in Quality of Life (QoL)

Changes in QoL from baseline will be collected for each subject and analyzed using the following questionnaires: 1) EQ-5D (measures general health status); and 2) VascuQoL (measures health-related QoL in PAD). The mean changes from baseline to follow up in QOL will be estimated for each study arm and treatment combinations in the context of a general linear model, which will account for repeated measurements upon a subject, and will attempt to quantify the relationship between covariates or sub-group effects and mean change.

Endpoint 5. Change in Six-Minute Walk Test (6MWT)

Changes from baseline to follow up results from the 6MWT will be analyzed by the Functional Core Laboratory (CPC Clinical Research, Aurora, CO) for each subject capable of

and willing to walk. This endpoint data will be collected for subjects enrolled under Rutherford classification 2-5. The mean changes from baseline in 6MWT will be estimated for each of the study arm and treatment combinations in the context of a general linear model, which will account for repeated measurements upon a subject, and will attempt to quantify the relationship between covariates or sub-group effects and mean change.

Endpoint 6. Economic Outcomes

Health care resource utilization and hospital billing data (UB-04 forms, itemized bills) from the index procedure and subsequent hospital- and/or clinic-based PAD treatment procedures will be collected and analyzed by the Health Economics Core Laboratory (David Cohen, Saint Luke's Hospital/Mid America Heart Institute, Kansas City, MO). The mean levels of utilization will be estimated for each of the study arm and treatment combinations in the context of a general linear model, which will account for repeated measurements upon a subject, and will attempt to quantify the relationship between covariates or sub-group effects and mean level of utilization.

Follow-up

All subjects will be followed from post-procedure to discharge, at 30 ± 15 days; at 6 months ± 30 days, at 12 months ± 60 days, at 18 months ± 30 days; at 24 months ± 60 days; and annually (± 60 days) thereafter until completion of the 5-year post-treatment follow-up or study termination, whichever occurs first. Follow-up visit windows will be calculated from the date of treatment of the index lesion(s) of the target limb. Office follow-up visits are required at 30 days and 6, 12, and 24 months post-treatment. All other visits can be conducted via telephone (see Table 2).

In situations where major amputation of the index limb occurs and the study subject is unable to return to the clinic for follow-up visits; phone visits can be performed by the qualified site personnel to obtain pertinent data. This may include, but is not limited to adverse event updates and QoL questionnaires.

Study Procedures

The required evaluations must be completed at the intervals specified in Table 3. The following diagnostic exams are required: peripheral arterial angiography of the target limb, Rutherford classification; ankle brachial index (ABI) and toe brachial index (TBI) of both limbs. In cases where TBI is not measurable, post-digit warming photoplethysmography (PPG) test can be performed.

Duplex ultrasonography (DUS) and wound assessment must be performed on the index limb only.

The EQ-5D and VascuQoL questionnaires are required to be completed by each subject at baseline and at the time of each study follow-up visit. Quality of Life questionnaires may be mailed to the subjects for completion for any scheduled visits conducted over the telephone.

Table 2: Summary of Study Required Tests and Follow-up Visits

Evaluation Baseline Procedure/ Discharge 30 Days 6 Months 12 Months 18 Months1 24 Months 3 4 and 5 Year

Visit Window Prior to index procedure as indicated ±15 days ±30 days ±60 days ±30 days ±60 days ±60 days

Informed consent Must be collected prior to study-r that are not considerec squired testing or procedures standard of care

Medical History, including Creatinine X <45 days

Rutherford classification X <30 days X X X X

Diagnostic peripheral • • $ angiogram images X <90 days

Peripheral arterial angiogram (during and post-treatment) X

ABI and TBI# X <90 days X X X X

PPG (where applicable)§ X <90 days X X X X

6MWTT (Rutherford 2-5 only) X <45 days X X X X

Wound assessment5 X <30 days X X X X

QoL questionnaires: EQ-5D and VascuQoL X <45 days X X X X X X

DUS (Rutherford 2-3 only) X X X X

Source

documentation

*This visit may be conducted over the telephone.

$Diagnostic images obtained within 3 months of index procedure may be utilized for assessment of baseline run-off.

#Bilateral ABI/TBI are required for Rutherford 2-6. For Rutherford 2-3 only: If ABI is measurable, TBI is recommended, but not required. When ABI is not measureable, TBI is required.

§PPG (photoplethysmography): In cases where TBI is not measurable, post-digit warming PPG test can be performed.

^Assessment should be conducted if subject is capable of walking.

Assessment may not apply at the subsequent visit if the wound has healed or was not present at baseline. ASite will submit requested source documentation to the Sponsor. Sponsor will review data entered by the site based upon the submitted source to meet the monitoring requirements of the study.

Data analysis

Analyses will be conducted on locked clinical study data using SAS version 9.2 or higher or other compatible analysis software. The primary analyses will be aimed at evaluating the clinical outcomes of patients undergoing lower extremity endovascular intervention in each study arm. The analyses will be conducted to describe and identify the predictors of adverse clinical outcomes (including both baseline clinical and angiographic variables). These predictive analyses of acute procedural and long-term outcomes are intended to determine the drivers of overall cohort outcomes and provide context for understanding the evaluations by treatments. Further analyses will be performed to compare outcomes between stent, atherectomy and angioplasty usage (including each unique atherectomy device) of a particular clinical cohort. These clinical cohorts are Rutherford 2-3, Rutherford 4-5, and Rutherford 6. Since this is an observational study, allocation to a particular treatment will not be random but rather based on site physician preference based on several clinical and PAD disease characteristics. Thus to allow for a comparison between treatments within a clinical cohort (Rutherford Class 2-3, 4-5, 6), a propensity score will be created that adjusts for the treatment decision. That score will then be utilized as a variable in the model used to compare outcomes between treatments. The

propensity scores will be created using available baseline data including patient demographics, limb hemodynamics (ABI), medical and vascular history and lesion characteristics (with particular attention to lesion length and calcification).

A final analysis will be performed once all subjects have been enrolled. Due to the nature and objectives of this observational study, not all of the analyses and summaries may be pre-specified. In particular, the development of the LIBERTY Patient Risk Score(s) will be conducted in an ad-hoc or a posteriori manner. Subjects' clinical, demographic and other parameters will be assessed to develop LIBERTY Patient Risk Score(s) to predict clinical outcomes and provide additional guidance for intervention in this patient population. LIBERTY patient risk scores will be developed to predict clinical outcomes deemed meaningful by the steering committee. One potential analysis we are planning is to first enter clinically meaningful variables into a univariable regression analysis, then use a multivariable stepwise regression analysis including all significant univariable predictors to assess variables that remain significant predictors of the outcome of interest on a multivariate level. In light of regional differences in PAD care and outcomes, geographical differences will be accounted for in the LIBERTY analysis16,23. In regards to hospital clustering, because of the high number of centers, correlation among subjects within geographical region will be accounted for in the analysis. This could be done either through hierarchical modeling or inclusion of a categorical regional variable.

For all analyses, a primary endovascular treatment and treatment location(s) will be defined within each study arm. These will be used as the basis for comparisons of treatment and treatment location as well as clinical and economic outcomes within the study arm. The primary and secondary specific analyses for descriptive purposes and planned outcome analyses will be performed as pre-specified in the analysis plan.

Baseline patient characteristics and risk factors will be presented by study treatment arm. This will include frequency distributions for categorical variables and summary statistics for continuous variables as appropriate. Comparisons between treatment groups for baseline characteristics will be propensity-score adjusted.

All study data will be collected using a database located on a secure server. Electronic case report forms will be utilized where possible. The study data will be reviewed by the Sponsor and queries will be generated to clarify data as necessary.

In addition to examining clinical and functional outcomes, one of the goals of this study is to investigate the costs and cost-effectiveness of endovascular treatment of PAD. To support these objectives, detailed data on health care resource utilization and costs will be collected for the index procedure and associated hospitalization(s) and for any additional procedures/hospitalizations required for treatment of PAD or its complications during the clinical follow-up period. Trained personnel from the Health Economics Core Laboratory will work in conjunction with each hospital's finance department to collect all relevant billing data. In order to facilitate this process, each site is required to provide a contact person in the finance department who is able to provide access to billing data. In addition, each subject will be required to sign a medical billing release form that allows personnel from the Health Economics Core Laboratory to collect the necessary billing data. Steering Committee

The organization and scientific conduct is supervised by an external Steering Committee. An external physician steering committee assisted with the design of the study. The Steering Committee is comprised of community and academic physicians. The main responsibilities of the committee are: providing recommendations for the study design and execution; providing input on the study protocol, case report forms and Data Analysis Plan; reviewing interim and final data analysis; and providing input on issues identified during the study execution. In addition, the Steering Committee along with one non-voting CSI representative comprise the Publication Committee whose role involves providing strategic guidance on publications and presentations that can be generated from data collected in LIBERTY Study. Four steering committee members also serve as the national principal investigators for the study; one for claudication arm (Rutherford 2-3; William Gray, MD), two for CLI arm (Rutherford 4-5; Gary Ansel, MD, George Adams, MD), and one for the CLI arm (Rutherford 6; Jihad Mustapha, MD).

DISCUSSION

There is a strong need for more clinical data on the appropriate management of real-world PAD patients. Historically, there has been a lack of direct comparison device studies, as well as randomized controlled trials that include high-risk patients with severe critical limb ischemia (Rutherford classification 6). This is likely due to the cost of conducting a trial and perceived risk by sponsors of potential undesirable outcomes of such trials on the future of their

devices. The need for such data is evidenced by ACC's NCDR recent PVI Registry, designed to ultimately optimize outcomes and improve care for PAD patients. However, unlike the NCDR PVI Registry, LIBERTY will collect data post 30-day follow-up (out to 5 years) and includes economic analysis, assessment of patient-centric outcomes (i.e. walking ability and QOL assessment), and core lab adjudication of data. These key design differences highlight the novelty and importance of the LIBERTY study.

The LIBERTY study is designed to study all PAD patients (Rutherford classification 2-6) receiving any endovascular treatment option. All efforts will be made to ensure that consecutive patients will be enrolled in the study regardless of the type of endovascular treatment that they may receive. Moreover, the inclusion/exclusion in this study has only basic limitations required for any research study (e.g., exclusion of patients <18 years old, pregnant women or anyone who is not willing or able to sign informed consent form).

The LIBERTY steering committee provides oversight, and the study utilizes numerous core laboratory adjudications and independent data analysis to increase clinical rigor and remove potential bias. This study also includes several unique PAD clinical data such as long-term follow-up, prospective quality of life and economic assessments. However, there are inherent limitations of the LIBERTY study due to the registry design, including lack of site randomization and lack of comparison to non-device therapies (i.e. bypass or medical management).

Utilizing such a unique data collection and analysis, the LIBERTY study will evaluate not only clinical but also economic outcomes of varied PAD procedures, details that are certainly becoming more important to our health care systems.

CONCLUSION

As endovascular options for PAD patients continue to expand, choice of revascularization must be considered in the context of the patient's clinical status, specific anatomic and lesion characteristics, and the optimal device features to ensure success. Future well-designed and executed randomized controlled trials that track clinically relevant outcomes, including the cost of the endovascular treatments and long-term outcomes will enable physicians to determine the optimal therapies for their patients with PAD. This will likely advance both treatments and outcomes for PAD patients. The LIBERTY study may help increase the understanding of the

clinical and economic outcomes of endovascular treatment for claudicants and CLI patients with infrapopliteal PAD. These data may lead to expanded national PAD registries and help to standardize PAD definition and treatment guidelines. Ultimately, this knowledge can inform future PAD clinical trials, provide data to help physicians choose the best therapy for patients, and advance the treatment of PAD.

Trial status

This study was initiated May 2013 and is currently enrolling patients. Enrollment is expected to be completed by 2016.

Acknowledgements

Financial support for the study is provided by Cardiovascular Systems, Inc.

thank Ann Behrens, B.S., and Zsuzsanna Igyarto, Ph.D. of Cardiovascular Systems editing and critical review of this manuscript.

Abbreviations

6MWT: Six Minute Walk Test

ABI: Ankle-Brachial Index

AT: Anterior Tibial

BA: Balloon Angioplasty

CFR: Code of Federal Regulations

CLI: Critical Limb Ischemia

CSI: Cardiovascular Systems, Inc.

DUS: Duplex Ultrasound;

eCRF: electronic Case Report Form

EDC: Electronic Data Capture

EQ-5D: EuroQol Quality of Life Questionnaire

FDA: Food and Drug Administration

GCP: Good Clinical Practices

IC: Intermittent Claudication

ICF: Informed Consent Form

IFU: Instructions for Use

IRB: Institutional Review Board

MAE: Major Adverse Event

MLD: Minimum Lumen Diameter

OAS: Orbital Atherectomy System

PAD: Peripheral Artery Disease

PI: Principal Investigator

The authors Inc, with

POP: Popliteal; PR: Peroneal

PT: Posterior Tibial

PTA: Percutaneous Transluminal Angioplasty

QoL: Quality of Life

SFA: Superficial Femoral Artery

TLR: Target Lesion Revascularization

TVR: Target Vessel Revascularization

TPT: Tibial Peroneal Trunk

US: United States

VascuQoL: Vascular Quality of Life Questionnaire

References

1. Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, Krook SH, Hunninghake DB, Comerota AJ, Walsh ME, McDermott MM, Hiatt WR. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001;286(11):1317-1324.

2. Schiavetta A, Maione C, Botti C, Marino G, Lillo S, Garrone A, Lanza L, Pagliari S, Silvestroni A, Signoriello G, Sica V, Cobellis G. A phase II trial of autologous transplantation of bone marrow stem cells for critical limb ischemia: results of the Naples and Pietra Ligure Evaluation of Stem Cells study. Stem Cells TranslMed. 2012;1(7):572-578. doi:10.5966/sctm.2012-0021.

3. Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, Jones DN. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg. 1997;26(3):517-538.

4. Liu J, Wu Y, Li Z, Li W, Wang S. Endovascular treatment for intermittent claudication in patients with peripheral arterial disease: a systematic review. Ann Vasc Surg. 2014;28(4):977-982. doi:10.1016/j.avsg.2013.05.022.

5. Hamburg NM, Balady GJ. Exercise rehabilitation in peripheral artery disease: functional impact and mechanisms of benefits. Circulation. 2011;123(1):87-97. doi:10.1161/CIRCULATI0NAHA.109.881888.

6. Jones WS, Schmit KM, Vemulapalli S, Subherwal S, Patel MR, Hasselblad V, Heidenfelder BL, Chobot MM, Posey R, Wing L, Sanders GD, Dolor RJ. Treatment Strategies for Patients With Peripheral Artery Disease. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013. http://www.ncbi.nlm.nih.gov/books/NBK148574/. Accessed October 7, 2015.

7. Guidon M, McGee H. One-year effect of a supervised exercise programme on functional capacity and quality of life in peripheral arterial disease. DisabilRehabil. 2013;35(5):397-404. doi:10.3109/09638288.2012.694963.

8. Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. JAMA. 1995;274(12):975-980.

9. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, Hiratzka LF, Murphy WR, Olin JW, Puschett JB, Rosenfield KA, Sacks D, Stanley JC, Taylor LM Jr, White CJ, White J, White RA, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Gibbons RJ, Halperin JL, Hiratzka LF, Hunt SA, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. J Am Coll Cardiol. 2006;47(6):1239-1312. doi:10.1016/j.jacc.2005.10.009.

10. Murphy TP, Cutlip DE, Regensteiner JG, Mohler ER, Cohen DJ, Reynolds MR, Massaro JM, Lewis BA, Cerezo J, Oldenburg NC, Thum CC, Goldberg S, Jaff MR, Steffes MW, Comerota AJ, Ehrman J, Treat-Jacobson D, Walsh ME, Collins T, Badenhop DT, Bronas U, Hirsch AT, CLEVER Study Investigators. Supervised exercise versus primary stenting for claudication resulting from aortoiliac peripheral artery disease: six-month outcomes from the claudication: exercise versus endoluminal revascularization (CLEVER) study. Circulation. 2012;125(1):130-139. doi:10.1161/CIRCULATIONAHA.111.075770.

11. Murphy TP, Cutlip DE, Regensteiner JG, Mohler ER, Cohen DJ, Reynolds MR, Massaro JM, Lewis BA, Cerezo J, Oldenburg NC, Thum CC, Jaff MR, Comerota AJ, Steffes MW, Abrahamsen IH, Goldberg S, Hirsch AT. Supervised exercise, stent revascularization, or medical therapy for claudication due to aortoiliac peripheral artery disease: the CLEVER study. J Am Coll Cardiol. 2015;65(10):999-1009. doi:10.1016/j.jacc.2014.12.043.

12. Frans FA, Bipat S, Reekers JA, Legemate DA, Koelemay MJW. Systematic review of exercise training or percutaneous transluminal angioplasty for intermittent claudication. Br J Surg. 2012;99(1):16-28. doi:10.1002/bjs.7656.

13. Fakhry F, Rouwet EV, den Hoed PT, Hunink MGM, Spronk S. Long-term clinical effectiveness of supervised exercise therapy versus endovascular revascularization for intermittent claudication from a randomized clinical trial. Br J Surg. 2013;100(9):1164-1171. doi:10.1002/bjs.9207.

14. Lepantalo M, Matzke S. Outcome of unreconstructed chronic critical leg ischaemia. Eur J Vasc Endovasc Surg Off J Eur Soc Vasc Surg. 1996;11(2):153-157.

15. Allie DE, Hebert CJ, Ingraldi A, Patlola RR, Walker CM. 24-carat gold, 14-carat gold, or platinum standards in the treatment of critical limb ischemia: bypass surgery or endovascular intervention? J Endovasc Ther Off J Int Soc Endovasc Spec. 2009;16 Suppl 1:I134-I146. doi:10.1583/08-2599.1.

16. Jones WS, Patel MR, Dai D, Subherwal S, Stafford J, Calhoun S, Peterson ED. Temporal trends and geographic variation of lower-extremity amputation in patients with peripheral artery disease: results from U.S. Medicare 2000-2008. J Am Coll Cardiol. 2012;60(21):2230-2236. doi:10.1016/j.jacc.2012.08.983.

17. Vemulapalli S, Greiner MA, Jones WS, Patel MR, Hernandez AF, Curtis LH. Peripheral arterial testing before lower extremity amputation among Medicare beneficiaries, 2000 to 2010. Circ Cardiovasc Qual Outcomes. 2014;7(1):142-150. doi:10.1161/CIRC0UTC0MES.113.000376.

18. Henry AJ, Hevelone ND, Belkin M, Nguyen LL. Socioeconomic and hospital-related predictors of amputation for critical limb ischemia. J Vasc Surg. 2011;53(2):330-339.e1. doi:10.1016/j.jvs.2010.08.077.

19. Shammas NW. Epidemiology, classification, and modifiable risk factors of peripheral arterial disease. Vasc Health RiskManag. 2007;3(2):229-234.

Anderson PL, Gelijns A, Moskowitz A, Arons R, Gupta L, Weinberg A, Faries PL, Nowygrod R, Kent KC. Understanding trends in inpatient surgical volume: vascular interventions, 1980-2000. J Vasc Surg. 2004;39(6):1200-1208. doi:10.1016/j.jvs.2004.02.039.

Rowe VL, Lee W, Weaver FA, Etzioni D. Patterns of treatment for peripheral arterial disease in the United States: 1996-2005. J Vasc Surg. 2009;49(4):910-917. doi:10.1016/j.jvs.2008.11.054.

Egorova NN, Guillerme S, Gelijns A, Morrissey N, Dayal R, McKinsey JF, Nowygrod R. An analysis of the outcomes of a decade of experience with lower extremity revascularization including limb salvage, lengths of stay, and safety. J Vasc Surg. 2010;51(4):878-885, 885.e1. doi:10.1016/j.jvs.2009.10.102.

Goodney PP, Travis LL, Nallamothu BK, Holman K, Suckow B, Henke PK, Lucas FL, Goodman DC, Birkmeyer JD, Fisher ES. Variation in the use of lower extremity vascular procedures for critical limb ischemia. Circ Cardiovasc Qual Outcomes. 2012;5(1):94-102. doi:10.1161/CIRCOUTCOMES.111.962233.